Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia

Autores
Marcora, Maria Silvina; Fernandez Gamba, Agata Claudia; Avendaño, Luz A; Rotondaro, Cecilia; Podhajcer, Osvaldo Luis; Vidal, Rubén; Morelli, Laura; Ceriani, Maria Fernanda; Castaño, Eduardo Miguel
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
BACKGROUND: Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI2 gene. Processing of the mutated BRI2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. RESULTS: By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri2-23 (the normal product of wild-type BRI2 processing) and amyloid-β (Aβ) 1-42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Aβ42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Aβ42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. CONCLUSIONS: Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Aβ42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.
Fil: Marcora, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Fernandez Gamba, Agata Claudia. Fundación Instituto Leloir; Argentina
Fil: Avendaño, Luz A. Fundación Instituto Leloir; Argentina
Fil: Rotondaro, Cecilia. Fundación Instituto Leloir; Argentina
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Vidal, Rubén. Indiana University School of Medicine. Indiana Alzheimer Disease Center. Department of Pathology and Laboratory Medicine; Estados Unidos
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Ceriani, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Materia
Alzheimers disease
Familial British dementia
Familial Danish dementia
ABri
ADan
Neurotoxicity
Drosophila
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/8479
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/8479
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementiaMarcora, Maria SilvinaFernandez Gamba, Agata ClaudiaAvendaño, Luz ARotondaro, CeciliaPodhajcer, Osvaldo LuisVidal, RubénMorelli, LauraCeriani, Maria FernandaCastaño, Eduardo MiguelAlzheimers diseaseFamilial British dementiaFamilial Danish dementiaABriADanNeurotoxicityDrosophilahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3BACKGROUND: Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI2 gene. Processing of the mutated BRI2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. RESULTS: By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri2-23 (the normal product of wild-type BRI2 processing) and amyloid-β (Aβ) 1-42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Aβ42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Aβ42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. CONCLUSIONS: Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Aβ42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.Fil: Marcora, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Fernandez Gamba, Agata Claudia. Fundación Instituto Leloir; ArgentinaFil: Avendaño, Luz A. Fundación Instituto Leloir; ArgentinaFil: Rotondaro, Cecilia. Fundación Instituto Leloir; ArgentinaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Vidal, Rubén. Indiana University School of Medicine. Indiana Alzheimer Disease Center. Department of Pathology and Laboratory Medicine; Estados UnidosFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Ceriani, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaBiomed Central2014-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8479Marcora, Maria Silvina; Fernandez Gamba, Agata Claudia; Avendaño, Luz A; Rotondaro, Cecilia; Podhajcer, Osvaldo Luis; et al.; Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia; Biomed Central; Molecular Neurodegeneration; 9; 5; 1-2014; 1-141750-1326enginfo:eu-repo/semantics/altIdentifier/url/https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-9-5info:eu-repo/semantics/altIdentifier/doi/10.1186/1750-1326-9-5info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898387/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:13Zoai:ri.conicet.gov.ar:11336/8479instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:49:13.912CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
title Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
spellingShingle Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
Marcora, Maria Silvina
Alzheimers disease
Familial British dementia
Familial Danish dementia
ABri
ADan
Neurotoxicity
Drosophila
title_short Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
title_full Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
title_fullStr Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
title_full_unstemmed Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
title_sort Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
dc.creator.none.fl_str_mv Marcora, Maria Silvina
Fernandez Gamba, Agata Claudia
Avendaño, Luz A
Rotondaro, Cecilia
Podhajcer, Osvaldo Luis
Vidal, Rubén
Morelli, Laura
Ceriani, Maria Fernanda
Castaño, Eduardo Miguel
author Marcora, Maria Silvina
author_facet Marcora, Maria Silvina
Fernandez Gamba, Agata Claudia
Avendaño, Luz A
Rotondaro, Cecilia
Podhajcer, Osvaldo Luis
Vidal, Rubén
Morelli, Laura
Ceriani, Maria Fernanda
Castaño, Eduardo Miguel
author_role author
author2 Fernandez Gamba, Agata Claudia
Avendaño, Luz A
Rotondaro, Cecilia
Podhajcer, Osvaldo Luis
Vidal, Rubén
Morelli, Laura
Ceriani, Maria Fernanda
Castaño, Eduardo Miguel
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimers disease
Familial British dementia
Familial Danish dementia
ABri
ADan
Neurotoxicity
Drosophila
topic Alzheimers disease
Familial British dementia
Familial Danish dementia
ABri
ADan
Neurotoxicity
Drosophila
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv BACKGROUND: Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI2 gene. Processing of the mutated BRI2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. RESULTS: By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri2-23 (the normal product of wild-type BRI2 processing) and amyloid-β (Aβ) 1-42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Aβ42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Aβ42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. CONCLUSIONS: Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Aβ42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.
Fil: Marcora, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Fernandez Gamba, Agata Claudia. Fundación Instituto Leloir; Argentina
Fil: Avendaño, Luz A. Fundación Instituto Leloir; Argentina
Fil: Rotondaro, Cecilia. Fundación Instituto Leloir; Argentina
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Vidal, Rubén. Indiana University School of Medicine. Indiana Alzheimer Disease Center. Department of Pathology and Laboratory Medicine; Estados Unidos
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Ceriani, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
description BACKGROUND: Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI2 gene. Processing of the mutated BRI2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. RESULTS: By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri2-23 (the normal product of wild-type BRI2 processing) and amyloid-β (Aβ) 1-42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Aβ42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Aβ42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. CONCLUSIONS: Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Aβ42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.
publishDate 2014
dc.date.none.fl_str_mv 2014-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
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info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/8479
Marcora, Maria Silvina; Fernandez Gamba, Agata Claudia; Avendaño, Luz A; Rotondaro, Cecilia; Podhajcer, Osvaldo Luis; et al.; Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia; Biomed Central; Molecular Neurodegeneration; 9; 5; 1-2014; 1-14
1750-1326
url http://hdl.handle.net/11336/8479
identifier_str_mv Marcora, Maria Silvina; Fernandez Gamba, Agata Claudia; Avendaño, Luz A; Rotondaro, Cecilia; Podhajcer, Osvaldo Luis; et al.; Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia; Biomed Central; Molecular Neurodegeneration; 9; 5; 1-2014; 1-14
1750-1326
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-9-5
info:eu-repo/semantics/altIdentifier/doi/10.1186/1750-1326-9-5
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898387/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Biomed Central
publisher.none.fl_str_mv Biomed Central
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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